NDLI: C-Terminal Mutants of Apolipoprotein L-I Efficiently Kill Both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense

Content Provider	PubMed Central
Author	Laurence, Lecordier Benoit, Vanhollebeke Poelvoorde, Philippe Patricia, Tebabi Paturiaux-hanocq, Françoise Andris, Fabienne Lins, Laurence Pays, Etienne
Editor	Mansfield, John M.
Abstract	Apolipoprotein L-I (apoL1) is a human-specific serum protein that kills Trypanosoma brucei through ionic pore formation in endosomal membranes of the parasite. The T. brucei subspecies rhodesiense and gambiense resist this lytic activity and can infect humans, causing sleeping sickness. In the case of T. b. rhodesiense, resistance to lysis involves interaction of the Serum Resistance-Associated (SRA) protein with the C-terminal helix of apoL1. We undertook a mutational and deletional analysis of the C-terminal helix of apoL1 to investigate the linkage between interaction with SRA and lytic potential for different T. brucei subspecies. We confirm that the C-terminal helix is the SRA-interacting domain. Although in E. coli this domain was dispensable for ionic pore-forming activity, its interaction with SRA resulted in inhibition of this activity. Different mutations affecting the C-terminal helix reduced the interaction of apoL1 with SRA. However, mutants in the L370-L392 leucine zipper also lost in vitro trypanolytic activity. Truncating and/or mutating the C-terminal sequence of human apoL1 like that of apoL1-like sequences of Papio anubis resulted in both loss of interaction with SRA and acquired ability to efficiently kill human serum-resistant T. b. rhodesiense parasites, in vitro as well as in transgenic mice. These findings demonstrate that SRA interaction with the C-terminal helix of apoL1 inhibits its pore-forming activity and determines resistance of T. b. rhodesiense to human serum. In addition, they provide a possible explanation for the ability of Papio serum to kill T. b. rhodesiense, and offer a perspective to generate transgenic cattle resistant to both T. b. brucei and T. b. rhodesiense.
Related Links	http://dx.doi.org/10.1371/journal.ppat.1000685
Starting Page	1000685
File Format	PDF
ISSN	15537374
e-ISSN	15537374
Journal	PLoS Pathogens
Issue Number	12
Volume Number	5
Language	English
Publisher	Public Library of Science
Publisher Date	2009-12-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Immunology Genetics Molecular Biology Microbiology Parasitology Virology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Virology Molecular Biology Parasitology Immunology Microbiology

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